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Copyright ERS Journals Ltd 1997
European Respiratory Journal
ISSN 0903 - 1936
Eur Respir J 1997; 10: 1332–1335
DOI: 10.1183/09031936.97.10061332
Printed in UK - all rights reserved
Pneumothorax in HIV-infected patients:
role of Pneumocystis carinii pneumonia and
pulmonary tuberculosis
M. Tumbarello*, E. Tacconelli*, T. Pirronti**, R. Cauda*, L. Ortona*
Pneumothorax in HIV-infected patients: role of Pneumocystis carinii pneumonia and
pulmonary tuberculosis. M. Tumbarello, E. Tacconelli, T. Pirronti, R. Cauda, L. Ortona.
©ERS Journals Ltd 1997.
ABSTRACT: Patients with acquired immune deficiency syndrome (AIDS) are at
increased risk for pneumothorax, which usually occurs in the setting of Pneumocystis
carinii pneumonia. The rationale of the present study was based on the hypothesis
that the increased incidence of pulmonary tuberculosis in human immunodeficiency virus (HIV)-infected patients could favour the development of pneumothorax
in such patients. A case-control study was performed comprising 140 HIV-infected patients grouped as follows: 35 patients with pneumothorax and 105 matched
controls without pneumothorax.
Univariate analysis identified four risk factors for pneumothorax: 1) previous
P. carinii pneumonia (p=0.01); 2) current P. carinii pneumonia (p=0.02); 3) pulmonary tuberculosis (p=0.01); and 4) cysts, pneumatoceles or bullae on chest radiographs (p<0.001). Multivariate analysis indicated that current P. carinii pneumonia
(p=0.01) and pulmonary tuberculosis (p=0.04) were both independent risk factors
for pneumothorax.
In conclusion, our findings demonstrate that, in addition to Pneumocystis carinii
pneumonia, pulmonary tuberculosis enhances the risk of pneumothorax in patients
with acquired immune deficiency syndrome.
Eur Respir J 1997; 10: 1332–1335.
The reported rate of spontaneous pneumothorax (PTX)
in patients with acquired immune deficiency syndrome
(AIDS) is 1–2%, and this percentage increases to 5–10%
in those patients with current or previous Pneumocystis
carinii pneumonia (PCP) [1–5]. It has been hypothesized
that in patients with acute PCP, the lung may rupture
as a consequence of parenchymal necrosis, or formation of pneumatoceles, presumably caused by a checkvalve effect in a peripheral airway. The cysts may also
be the consequence of healing and fibrosis, and, if they
are overdistended, may rupture with possible PTX [6, 7].
In addition, these pulmonary lesions may also persist
after recovery from PCP, and cause PTX in some patients [3, 7]. Cysts or bullous lung diseases have also been
observed in human immunodeficiency virus (HIV)-infected patients, who have previously received aerosolized pentamidine for PCP prophylaxis and who have later
developed PTX [8]. However, the occurrence of PTX in
patients with PCP previously under pentamidine prophylaxis may simply reflect a complication of PCP secondary to failure of prophylaxis [9]. Rarely, PTX has
also been reported in HIV-infected patients as a consequence of respiratory infections caused by agents other
than P. carinii, e.g. Mycobacterium tuberculosis or Mycobacterium avium complex, Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa and
Cytomegalovirus, or it has been associated with pulmonary Kaposi's sarcoma [2, 5].
Depts of *Infectious Diseases and **Radiology, Catholic University, Rome, Italy.
Correspondence: M. Tumbarello
Istituto Clinica Malattie Infettive
Università Cattolica Sacro Cuore
Largo Gemelli 8
00168 Roma
Italy
Keywords: Acquired immune deficiency
syndrome
Pneumocystis carinii pneumonia
pneumothorax
tuberculosis
Received : December 10 1996
Accepted after revision February 24 1997
This work has been partially supported by
the first Project on Tuberculosis (Istituto
Superiore di Sanità/Ministero della Sanità,
Roma).
Although the incidence of pulmonary tuberculosis, a
well-recognized primary cause of spontaneous PTX in
immunocompetent patients [10], has progressively increased worldwide in patients with HIV infection during
the last decade [11], PTX has been surprisingly infrequently reported in these patients [2, 5]. To further investigate the role of tuberculosis in PTX development in
HIV-infected patients, we analysed the risk factors, the
clinical and radiological findings and the outcome of
PTX in 35 patients with AIDS, using a univariate and
multivariate statistical approach.
Materials and methods
Patients
A retrospective review of the medical and radiological charts of all hospital admissions of HIV-infected
patients to our ward was completed from January 1987
to December 1995. For the purpose of this study, PTX
was defined as the radiographic evidence of a lung collapse. Any individual HIV-infected patient who had PTX
was considered as a case. In total, 3,522 medical records
of 2,691 HIV-infected patients were reviewed, and 42
episodes of PTX were identified in 38 patients. None
of the patients had a history or physical evidence of
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P N E U M O T H O R A X I N A I D S PAT I E N T S
chest trauma. One patient developed PTX after insertion of a central venous catheter and two patients (with
severe PCP) were receiving continuous positive airway
pressure when PTX developed. These three cases were
not included in the analysis, and a final number of 39
episodes observed in 35 patients was evaluated in the
study (Group A).
Each Group A patient was matched with three control HIV-infected patients (n=105; Group B), who had
the following characteristics: 1) no evidence of PTX; 2)
same sex and age (within 3 yrs); 3) hospitalization in
the same ward on the month of the diagnosis of the matched case; and 4) same stage and category of HIV infection [12]. Medical records of the study patients were
reviewed for the following data: HIV risk behaviour;
history of opportunistic infections; time from AIDS diagnosis; antiretroviral therapy; prophylaxis for PCP; and
risk factors for PTX. These latter included: intravenous
drug addiction; presence of coexisting pulmonary diseases; history of aerosol pentamidine use; number of previous episodes of PCP; smoking habits (a patient was
considered as a smoker if he/she had smoked more than
10 packs·year-1); chronic obstructive pulmonary disease
(COPD); and asthma.
The majority of the patients (126 out of 140; 90%)
were under primary or secondary PCP prophylaxis with
co-trimoxazole or dapsone, or pentamidine aerosol. A
patient was considered to be receiving aerosolized pentamidine if he/she had received at least three doses of
the drug. In patients with current respiratory failure, the
arterial oxygen tension and the fraction of inspired oxygen at the time of gas sampling were obtained. In all
patients with PTX, the clinical and radiographic findings,
treatment and outcome of PTX were also analysed. A
recurrence was defined as the development of a new PTX
more than 5 days after the recovery from the first one.
Diagnosis of PCP was made by identification of P.
carinii cysts using an immunofluorescence assay in specimens obtained from induced sputum or bronchoalveolar lavage (BAL). Diagnosis of pulmonary tuberculosis
was achieved by the isolation of M. tuberculosis from
induced sputum or BAL. Diagnosis of bacterial pneumonia was considered if bacteria (other than Mycobacteria) were isolated from induced sputum or BAL, or
from blood, in patients with respiratory symptoms and
parenchymal infiltrates on chest radiographs.
On chest radiographs, PTX was defined according to
the size of the collapsed lung, as: small (<15%); moderate (15–50%); and large (>50% of the collapsed lung).
Air-containing pulmonary lesions with very thin walls (<
2 mm) were referred to as "pneumatoceles". Progression
of the cysts or pneumatoceles was documented by comparison with previous chest radiographs and/or computed tomography (CT) scan.
Statistical analysis
Differences in means were tested for normal distribution and compared using Student's two-tailed t-test.
Differences in group proportions were assessed using
Chi-squared test or, for small numbers, using Fisher's
exact test. Potential risk factors for PTX were analysed
by univariate methods to screen for possible inclusion
into multivariate models. Multivariate analysis was per-
formed with logistic regression models, and 95% confidence intervals (95% CIs) were used to determinate the
statistical significance of the odds ratio (OR). Multivariate
analysis was performed to account for colinearity of
variables, adjust for simultaneous exposures, reveal any
interactions between these exposures, and determine a
multivariate OR for each factor. Age and sex were not
found to be confounders. The population attributable
risk (PAR), a crude estimate of all PTX ascribed to pulmonary tuberculosis, was calculated as the percentage
of the population risk which is attributable to the exposure. Two-tailed tests of significance at the p<0.05 level
were used to determine statistical significance.
Results
The rate of PTX was 11.2 per 1,000 hospital admissions for HIV infection. In particular, the episode prevalence of PTX in HIV-infected patients with PCP was
9.5%, and 6.8% in those with pulmonary tuberculosis.
The demographic data of cases and controls are summarized in table 1. PTX occurred in 23 patients (66%)
with PCP, which was current in nine of the 23 patients
(39%) and previous in 14 out of 23 (61%). Thirteen patients (37%) suffered from pulmonary tuberculosis; 11 of
the 13 patients (85%) had tuberculosis diagnosed prior
to development of PTX (median 3 months), and two patients (15%) at the same time as PTX. One of the patients
with pulmonary tuberculosis had suffered from a previous episode of PCP.
As regards the clinical findings of PTX, three patients
were asymptomatic (9%), 24 complained of chest pain
(69%), 17 dyspnoea (49%), 14 cough (40%), and 10 had
fever (>38˚C) (29%).
Statistical analysis of risk factors
Univariate analysis identified four factors significantly
associated with PTX: 1) previous PCP (p=0.01); 2) current PCP (p=0.02); 3) pulmonary tuberculosis (p=0.01);
and 4) presence of radiological alterations of the lung,
i.e. cysts, pneumatoceles or bullae on chest radiographs
(p<0.001) (table 2).
Development of PTX did not correlate with the severity of the concomitant episode of PCP, corticosteroid
Table 1. – Demographic data of 35 HIV-infected patients
with PTX (cases, i.e. Group A) and 105 matched HIVinfected patients (controls, i.e. Group B)
Sex males/females
Age yrs
HIV risk factor
Intravenous drug abuse
Homosexual contacts
Heterosexual contacts
Haemophilia
Stage of HIV infection*
C2
C3
Number of CD4+ T-cells·mm-3
Group A
Group B
32/3 (91/9)
33±4
96/9 (91/9)
33±6
25
5
4
1
(71)
(14)
(11)
(3)
2 (6)
33 (94)
58.3±63.7
79
15
10
1
(75)
(14)
(10)
(1)
6 (6)
99 (94)
62.5±59.9
Data are presented as number of patients and percentage in
parenthesis, or as mean±SD. *: according to the CDC classification of HIV infection [12]. HIV: human immunodeficiency
virus; PTX: pneumothorax; CDC: Centers for Disease Control.
M . TUMBARELLO ET AL .
1334
Table 2. – Univariate analysis of risk factors for PTX:
HIV-infected patients with PTX (Group A) compared to
HIV-infected patients without PTX (Group B)
Risk factors
for PTX
Group A Group B p-value
OR
n (%)
n (%)
(95% CI)
Previous PCP
14 (40)
18 (17)
0.01
Current PCP
9 (26)
10 (9)
Pentamidine
prophylaxis
Pulmonary
tuberculosis
Bacterial pneumonia
Cysts/bullae/
pneumatoceles
Intravenous drug
addiction
Pulmonary Kaposi's
sarcoma
NTM infections
Smoking
(>10 packs·yr-1)
Asthma
COPD
4 (11)
18 (17)
3.22
(1.27–8.17)
0.02
3.28
(1.08–9.96)
NS
-
13 (37)
17 (16)
0.01
3 (9)
27 (77)
13 (12)
34 (32)
25 (71)
79 (75)
1 (3)
4 (4)
NS
-
2 (6)
18 (51)
6 (6)
59 (56)
NS
-
1 (3)
1 (3)
1 (1)
1 (1)
NS
3.05
(1.18–7.88)
NS
<0.001
7.04
(2.69–18.98)
NS
-
NS
NS
-
PTX: pneumothorax; n: number of patients; PCP: Pneumocystis
carinii pneumonia; NTM: nontuberculous mycobacteria; COPD:
chronic obstructive pulmonary disease; NS: nonsignificant; OR:
odds ratio; 95% CI: 95% confidence interval.
treatment, number of episodes of previous PCP (one in
12 patients and two in two patients), and the time from
the previous episode of PCP (mean 6.4 months, range
2–23 months). The onset of PTX was also unrelated to
PCP prophylaxis with aerosolized pentamidine, HIV
risk behaviour (including intravenous drug abuse), smoking habits, asthma, COPD, bacterial pneumonia, AIDSrelated diseases (such as pulmonary Kaposi's sarcoma
and nontuberculous mycobacterial (NTM) infections),
time from AIDS diagnosis, and antiretroviral therapy.
The logistic regression analysis indicated that, among
the conditions selected by univariate analysis, only current PCP (p=0.01; OR=48.42; 95% CI=2.31–1015.0)
and pulmonary tuberculosis (p=0.04; OR=9.73; 95% CI=
2.74–126.7) were independent risk factors for the development of PTX. The PAR for pulmonary tuberculosis
to the AIDS population was 24%.
Radiology
On chest radiographs, five episodes were characterized by small (14%), 13 by moderate (37%) and 13 by
large (37%) PTX. In the remaining four episodes (11%),
tension PTX occurred, determining a shift of the heart
and mediastinum to the contralateral side, with a flattening of the cardiomediastinal contour and a depression of
the ipsilateral hemidiaphragm. Bilateral pneumothorax
occurred in three cases (9%). One patient with previous
PCP and pulmonary tuberculosis had haemopneumothorax, and one patient with S. aureus pneumonia and
prior PCP suffered from pyopneumothorax.
Eight of the nine patients with current PCP (89%) had
diffuse bilateral and fairly symmetrical fine reticular heterogeneous opacities. Five of the 14 patients with previous PCP (36%) and three of the nine with current PCP
(33%) had pneumatoceles throughout both lungs. Two of
the 14 patients with previous PCP (14%) and three of the
nine with current PCP (33%) had apical cysts detected
on chest radiographs prior to PTX development. Two of
the nine patients with current PCP (22%) had subpleural cysts detected only by radiographs in the presence of
PTX. Ten of the 13 patients with pulmonary tuberculosis (77%) had coarse interstitial densities and five of the
13 (38%) had hilar or mediastinal adenopathy. Bullae
were observed in 10 of the 13 patients with pulmonary
tuberculosis (77%). Two of the 13 patients with tuberculosis (15%) had a cavernous lesion of the right lower lobe.
Three patients with prior PCP and active bacterial pneumonia had parenchymal infiltrates on chest radiographs.
One patient with current PCP and Kaposi's pulmonary
sarcoma had severe bilateral heterogeneous densities.
CT scan, performed in 23 patients, documented the presence of cysts; in the upper lobes in 15 of the 23. Three
patients (9%) had normal chest radiographs prior to the
development of PTX.
Treatment and clinical outcome
Five patients with asymptomatic small PTX were successfully treated with observation and oxygen. Thirty
patients with moderate and large PTX were treated with
thoracostomy drains, inserted with large bore (36F) plastic intercostal chest tubes, connected either to an underwater seal or to suction. This therapeutic approach was
successful in 20 out of 30 patients (67%). Four of the 30
patients (13%), in whom PTX failed to completely resolve
with simple chest tube management, were treated with
chemical pleurodesis (with bleomycin solution via the
chest tube), and three of them (75%) completely resolved.
None of the patients needed surgical intervention. The
average time required to achieve a successful response to
any (including conservative) treatment was 11 days, ranging 3–18 days. Four patients developed a second episode
of PTX, 5 months (as a median) after the first. Two of
these patients suffered from bilateral and tension PTX.
The overall mortality was 23%. In particular, seven
patients died in the course of the first episode of PTX
and two in a recurrence. Bilateral PTX was not significantly associated with hastened mortality, although the
value was close to statistical significance (p=0.06).
Discussion
The occurrence of PTX in HIV-infected patients was
first reported in 1984 [1], and since then several other
reports [2–5] have indicated that patients with AIDS are
at increased risk of spontaneous PTX. Different causes
have been implicated in the development of PTX in patients with AIDS, namely: P. carinii infection [6, 7, 13–16];
HIV itself, which can cause (probably through different
mechanisms) a destructive action on the lung parenchyma, with alveolitis and "premature emphysema" [17]; and
aerosolized pentamidine for PCP prophylaxis [8, 9]. It
has been suggested that aerosolized pentamidine leaves
the apical areas of the lung untreated, and, if PCP develops, there is a progressive apical disease with large subpleural cavities, which may rupture and cause PTX [8].
However, contrary to previous reports [8, 9], our data do
not confirm the increased incidence of PTX in patients
receiving prophylaxis with aerosolized pentamidine.
In the present study, the rate of PTX was 11.2 per
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P N E U M O T H O R A X I N A I D S PAT I E N T S
1,000 hospital admissions for HIV infection. This rate
greatly exceeds the overall incidence of spontaneous PTX
in immunocompetent patients, which is estimated to be
about 0.06 per 1,000 hospital admissions per year [4,
18]. In particular, the present study indicates that the
episode prevalence of PTX in patients with PCP is 9.5%,
and 6.8% in those with pulmonary tuberculosis. The first
percentage confirms the association, already reported [1,
4, 11], of spontaneous PTX with current or previous
PCP in patients with AIDS. As a novel observation, the
present study indicates an increased frequency of PTX
in patients with AIDS and pulmonary tuberculosis. This
result is further confirmed by the percentage of the population attributable risk, which indicates that more than
20% of PTX incidence in the AIDS population could
be linked to the presence of pulmonary tuberculosis. Indeed, the association of pulmonary tuberculosis and PTX
is not infrequently reported in immunocompetent hosts
as a consequence of the rupture of subpleural blebs or
a tuberculous cavity into the pleural space. However,
these conditions do not seem to be frequent in HIVinfected patients, and they were responsible for development of PTX in only a few of the present patients. As
a pathogenic mechanism, it is possible that M. tuberculosis, either directly or through the activation of pulmonary macrophages (possibly in association with HIV), may
induce a chronic inflammatory reaction at the bronchiolar level, which causes obstruction, hyperinflation, progressive alveolar rupture and, finally, in some cases, PTX.
Based on the results of our retrospective analysis, we
can suggest that the increased rate of spontaneous PTX
observed in HIV patients with pulmonary tuberculosis,
independently from PCP or PCP prophylaxis, is the direct consequence of the growing number of HIV patients
with tuberculosis observed worldwide. Prospective studies are, however, required to further confirm the association of pulmonary tuberculosis with PTX in patients
with AIDS.
The statistically significant relationship of PTX and the
presence of radiographic alterations of the lungs (cysts,
pneumatoceles and bullae) in patients without PCP, could
indicate that these lesions are important predictors of
the risk of PTX. In fact, in association with the loss of
interalveolar and anchoring septa in the lung periphery,
the interstitial inflammatory and fibrotic reactions can
cause cystic degenerative evolution, which predisposes
the patients to formation of bullae or cavernous areas
with subsequent spontaneous rupture and PTX.
Surprisingly, the mortality of the present patients with
AIDS and PTX was lower than that indicated in previous reports [3, 19], and the presence of bilateral PTX
was not associated with hastened mortality, although the
value was close to statistical significance. Although it
is difficult to explain these differences in mortality, it
is possible to speculate that the variable distribution of
opportunistic infections and neoplasms in the present
study compared to previous reports [9, 19] could have
influenced the mortality.
In conclusion, this 9 yr retrospective survey confirms
that pneumothorax is not infrequently observed in human
immunodeficiency virus-infected patients, particularly
in the setting of Pneumocystis carinii pneumonia, and
it highlights a possible aetiological role of pulmonary
tuberculosis in the development of pneumothorax. Due
to the emerging importance of tuberculosis in human
immunodeficiency virus-infected subjects, we recommend that pneumothorax should be considered in all patients with pulmonary tuberculosis who deteriorate acutely
with worsening dyspnoea.
Acknowledgement: The authors are indebted to colleagues in the Department of Microbiology for their support.
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